The General Assembly of United Nations unanimously passed the resolution 61/225 to declare that diabetes as a global health concern and one of the major health challenges of the 21St century. According to the International Diabetes Federation (IDF) and the Baker IDI Heart, currently 285 million people are affected by this debilitating disease, and the figure will be projected to be 438 million by 2030. Until now, genetic predisposition and behavioral and environmental factors were considered as potential contributors, but recently epigenetic influences, such as the impact of in-utero effects and the maternal milieu, particularly in type II diabetes have been recognized as equally important risk factors. Therefore, coordinated efforts have been made in the west for the prevention and treatment of the disease (Zimmet P Z, et al., 2011).
Diabetes mellitus is characterized by elevated blood sugar levels. Hyperglycemia is the significant factor in causing non-enzymatic glycation of amino groups of body proteins, which lead to the formation of irreversible, reactive advanced glycation end-products (AGEs). The Maillard reaction or non-enzymatic glycation of proteins was initially identified by a French scientist, Louis Maillard in 1912. The reaction was initially investigated in food stuff, as heating, processing and storage and is associated with a variety of food-related phenomena, such as color, flavor and aroma. The reaction was later investigated in diabetic individuals after the discovery of glycated hemoglobin (HbA1c). Therefore, the Maillard reaction is analyzed in many fields due to its chemical, toxicological and pathophysiological properties (Wu C H, et al., 2011; Peyrous J, et al., 2006).
The Maillard reaction is a complex cascade of reaction and follows the similar pattern of free-radical chain reaction (Wu C H, et al., 2011). It is generally comprised of three stages:
Initiation Reaction: The carbonyl group of reducing sugars, such as glucose, fructose and ribose reacts non-enzymatically with the free amino groups of peptides, proteins, nucleic acid and lipids to form Schiff base, which is followed by a relatively stable product recognized as an Amadori product or ketoamine. The reaction equilibrium is greatly dependent on concentration of the initiation substrate and the duration of exposure, therefore the reaction is reversible till the formation of Amadori product (Peyrous J, et al., 2006).
Propagation Reaction: The ketoamine (Amadori product) either regenerates amines via metal ion-induced catalysis and oxygen-mediated oxidation or interacts with the amino acids, which results in the formation of carboxymethyl lysine (CML), while the dehydration of glycosyl group leads to the formation of highly reactive carbonyl intermediate 3-deoxyglucosone (DG) (Wu C H, et al., 2011).
Advanced Stage: The reactive carbonyl intermediate 3-DG interacts with the lysine residue of proteins, which results in the formation of pyrraline, an advanced glycation end-product (AGE). The stage also involves the reaction between pentose and lysine and arginine residues of proteins to form pentosidine (AGE) or other adducts. As a consequence, intra- and intermolecular cross-linking of proteins and fragmentation processes occur, which lead to the irreversible protein damages and denaturation. Besides these, other types of AGEs, which are also derived from the intermediate stage of the Maillard reaction, have been identified, including glyoxal-lysine dimer (GOLD), methylglyoxal-lysine dimer (MOLD), carboxyethyl-lysine dimer (CEL). These AGEs are highly heat stable and constitute the ultimate stage of the Maillard reaction (Wu C H, et al., 2011).
AGEs have been involved in the pathophysiology of many late complications of diabetes, such as diabetic micro- and macro vascular complications, including neuropathy, nephropathy, retinopathy and peripheral vascular diseases, stroke and myocardial infarction (Gutierrez R M P, et al., 2010). Although the mechanism involved in the pathogenesis of diabetic late complications is not completely understood, but many features have been examined, such as protein glycation results in the formation and accumulation of tissue AGEs, and hence irreversibly alter the structural and functional chemistry of affected proteins; the interaction of AGEs with their receptors known as RAGE (receptors for advanced glycation end-products) which are expressed on many cell types and up-regulated under hyperglycemic conditions, results in the generation of intracellular oxidative stress and induction of many proinflammatory cytokines, which lead to intracellular derangements in biological systems (Wu C H, et al., 2011).
The first identified AGEs inhibitor, aminoguanidine is a synthetic small hydrazine analog, has shown inhibitory potential in the formation of AGEs and has been used in phase III clinical trials for the treatment of diabetic nephropathy. Unfortunately, the trail has been terminated because of its undesirable side effects, such as gastrointestinal disorders, anemia and flu-like symptoms (Adisakwattana S, et al., 2012). These side effects perhaps due to the sequestration of pyridoxal group, which lead to the deficiency of vitamin B6 (Gutierrez R M P, et al., 2010).